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• W2094697718 abstract "Our ability to dissect immune pathways with the advent of molecular, cellular, and immunological techniques has led to a significant number of breakthrough discoveries over the past quarter century that have established our current paradigms of cellular and developmental immunology. The more recent application of genome-wide genetic association scans, gene expression microarrays, and proteome analysis to interrogate human tissue has revealed the marked complexities and heterogeneity of human autoimmune diseases, as well as defined pathways that are dominant in patient subsets of diseases. As examples, the genome-wide single nucleotide polymorphism (SNP) analysis of Crohn's disease has revealed the potential importance of nucleotide oligomerization domain 2 (NOD2) and the interleukin-23 (IL-23) receptor pathways in subsets of patients, mRNA microrarray analyses have suggested the importance of interferon-regulated genes in systemic lupus erythematosus, and proteome analyses of brain plaques have implicated the clotting cascade in multiple sclerosis. This convergence of knowledge of immunologic pathways coupled with our ability to interrogate the dysregulated components in human diseases has accelerated and broadened our ability to identify appropriate drug discovery targets. Indeed, this is an exciting time in drug discovery as the biologies of human diseases are being uncovered. In this issue, we review a microcosm of drug discovery targets that range from clinically validated to more speculative, but promising, pathways in human disease. The subjects are by no means a complete list of the areas that are ripe for drug discovery and development, and the topics are, in part, mitigated by the length of this edition as well as availability of authors' schedules. Nonetheless, this edition provides a glimpse of the current status of targeted therapies for immunologic diseases. The first section (1-7) will deal with targeting cytokines and secreted proteins, as this strategy has been well established over the past decade with the Federal Drug Administration (FDA) approval of therapies that neutralize tumor necrosis factor (TNF) and IL-1. The second section (8-13) includes therapies that are directed towards targeting cell types including T cells, B cells, as well as T–B-cell interactions. The third section (14-16) concerns therapies directed towards cellular trafficking. The fourth section (17, 18) is centered on therapies directed on innate immunity including Toll-like receptors and complement. The final section (19-23) includes more recent strategies to modify the immune response, including activating immune responses for treatment of infectious diseases, establishing tolerance, and cellular therapies. It will be of great interest to revisit and compare the landscape of immunotherapy a decade henceforth to understand how these paradigms may evolve and the field progresses. Finally, while the therapeutic target landscape is rich and the number of therapies that ultimately prove effective and safe will represent a select few, our ability to define patients who will best benefit from specific therapies has greatly lagged. Only approximately 40% of patients treated with TNF-neutralizing therapies achieve an ACR50 response score (a clinical composite of both objective and subjective criteria approximating 50% improvement). While we already have three FDA-approved anti-TNF therapies in the United States with at least an equal number of additional anti-TNF biologic therapies in development, we have little ability to predict, despite all of our technological advances, which patient will respond best to TNF neutralization. In my view, this is an area of dire unmet medical need. Much additional work needs to parallel drug discovery and development efforts, because progress in this area of investigation will truly benefit patients and improve the societal costs of medical care." @default.
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• W2094697718 date "2008-06-01" @default.
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• W2094697718 title "A golden era of opportunity in immunotherapy discovery and development" @default.
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• W2094697718 doi "https://doi.org/10.1111/j.1600-065x.2008.00642.x" @default.
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